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We present a leave-one-dataset-out meta-analysis defining generalizable intestinal disease signatures in mammalian hosts. Analyzing 512 samples from four bovine diarrhea and three canine IBD studies, we identified 12 bovine and 8 canine stable signature genera marked by depleted short-chain fatty acid (SCFA) producers and enriched pathobionts through a compositional random-effects framework with per-study covariate-adjusted effect sizes. A minimal signature set matched full-feature models across five machine learning models, and study-aware transfer learning improved cross-study generalization. Across 367 samples, signatures outperformed for intestinal versus non-intestinal phenotypes in cross-disease prediction. Cross-host validation across equine, feline, caprine, swine, and human datasets (533 animal and 1,182 human samples) revealed canine IBD-associated signatures outperformed in feline intestinal disease prediction, while bovine diarrhea-associated signatures generalized better to herbivorous hosts and human intestinal diseases. These findings may support the existence of conserved microbial signatures across veterinary and human medicine, warranting further investigation toward diagnostic applications.<\/jats:p>","DOI":"10.1038\/s42003-026-10647-5","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:25:50Z","timestamp":1784028350000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Toward disease-associated fecal microbiome signatures for domestic mammals"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8064-5666","authenticated-orcid":false,"given":"Dan","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Ganda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Silverman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiating","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine Rose","family":"Gottwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6538-8428","authenticated-orcid":false,"given":"Haowen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puchun","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5654-9172","authenticated-orcid":false,"given":"Jessica Anne Allerton","family":"McArt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"10647_CR1","doi-asserted-by":"publisher","first-page":"263ra158","DOI":"10.1126\/scitranslmed.3009759","volume":"6","author":"V Braniste","year":"2014","unstructured":"Braniste, V. et al. 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